Aging-related diseases, including neurodegeneration, cardiovascular diseases, cancer, and type II diabetes, are becoming the most severe health burden in the US. The long-term goal of the laboratory is to elucidate how autophagy is involved in aging and aging related diseases, and to develop pharmacological interventions to prevent, delay, or even reverse these pathological conditions. There is increasing evidence that mitochondrial dysfunction plays a critical role in accelerating the aging process and contributes to the aging-related diseases. One way that dysfunctional mitochondria are eliminated is through autophagy, a membrane trafficking process resulting in lysosomal degradation. Recent studies indicate that the capacity of autophagy decreases with age, which leads to the development of the mitochondrial-lysosomal axis theory of aging. The central feature of this hypothesis is that a reduction of autophagic capacity with age contributes to the accumulation of dysfunctional mitochondria, which in turn accelerates various pathological processes associated with aging. While attractive, the mitochondrial-lysosomal axis theory of aging has never been rigorously tested in mammals due to the lack of suitable experimental systems. Recently we and our collaborators have generated mouse models that either lack autophagy activity or have a reduced autophagic capacity. They will allow us to test this hypothesis in a direct and definitive way. The overall goal of this proposal is to test the mitochondrial-lysosomal axis theory of aging in mammals. There are three specific aims: (1). to determine the contribution of autophagy to mitochondria degradation, (2). to determine whether autophagy deficiency has a functional impact on mitochondrial biology, (3) to determine whether autophagic capacity is a rate-limiting factor such that a quantitative reduction of autophagic capacity with age accelerates the accumulation of dysfunctional mitochondria in mice. This study will help define the role of autophagy in the normal mammalian aging process, which could lay a solid foundation for a new strategy of aging intervention, i.e., delaying aging by activating autophagy. The proposed study is to elucidate how damaged mitochondria, a direct cause of aging and aging related diseases such as cancer and neurodegeneration, are accumulated. Successfully carrying out the proposed study would provide new venues for prevention and treatment of these aging-related diseases.